In 1989, Chiron Corporation (U.S.A.) cloned a gene fragment of human hepatitis virus which had been heretofore referred to as “non-A non-B hepatitis virus,” and the fragment was named “HCV” (SCIENCE, Vol. 244, 359–362, 1989). HCV is a virus, the genome of which is single strand (+) strand RNA. Besides Chiron Corporation, Shimotohno et al. of the National Cancer Center (Proc. Natl. Acad. Sci. USA, Vol. 87, 9524–9528, 1990) and Takamizawa et al. of the Research Institute for Microbial Diseases at Osaka University (J. Virol, Vol. 65, No. 3, 1105–1113, 1990) thereafter published the entire gene sequences of hepatitis C virus. Thereafter, it was found that HCV comprise three types of structural proteins, i.e., core protein, envelope 1 protein (hereinafter sometimes referred to as “E1” or “E1 protein”) and envelope 2 protein (hereinafter sometimes referred to as “E2/NS1” or “E2/NS1 protein”) and 6 types of non-structural proteins.
Once HCV is developed, acute hepatitis, chronic hepatitis, and hepatocirrhosis are highly likely to be developed, and the disease condition is eventually transited to liver cancer leading a patient to death. Conventionally, interferon, an anti-viral agent, has been typically used in the treatment. However, there are problems of variation in the therapeutic effects for each patient and side effects such as fever (J. Med. Virol., Vol. 42, 299–305, 1994) (Journal of Gastroenterology, Vol. 91, 995–1002, 1994).
Although a treatment using other anti-viral agents such as ribavirin has been also studied, this could not provide sufficient effect (Lancet, Vol. 337, 1058–1061, 1991), and therefore the development of a novel anti-HCV agent has been awaited.
HCV gene is considered to very easily undergo mutation and HCV, because of its high mutation ability, was presumed to escape from the immunity in the body of a patient. In particular, at the N-terminus of E2/NS1 of HCV, there is presumed to be a region of 25 to 30 amino acids, referred to as a “hyper variable region,” which is rich in mutation, and Kato et al. deduce that an epitope of a human immune system is a hyper variable region (J. Virol., Vol. 67, No. 7, 3923–3930, 1993) (J. Virol., Vol. 68, No. 8, 4776–4784, 1994). More specifically, since the region which is recognized by the human immune system such as neutralizing antibody is in the hyper variable region, even though the neutralizing antibody is generated in the body of the infected patient, it is considered that the hyper variable region immediately undergoes mutation and viruses escape from the antibody. However, Ishii et al. have reported that an antibody which inhibits the binding between E2/NS1 and human T cell Molt-4 is present in a highly active state only in the blood of a patient who naturally recovered from HCV, and it is suggested that a humoral immunity is involved in the treatment of HCV in spite of the high mutation ability of HCV (Hepatology, Vol. 28, No. 4, 1117–1120, 1998).
In 1999, Chiron Corporation (U.S.A.) isolated CD81 as a protein on a cell surface to which E2/NS1 bound (SCIENCE, Vol. 282, 938–941, 1999). CD81 and E2/NS1 which were expressed in Escherichia coli, bound to each other in the same manner as reported by Ishii et al. and the serum of a patient who naturally recovered from HCV inhibited this binding. This result suggested that CD81 was a receptor of HCV.
From the foregoing, it has been considered that the use, as an agent, of a substance such as an antibody, which binds to an envelope protein that is presumably deeply involved in the infection of HCV to a cell and inhibits the binding to a human cell infectious with HCV, can inhibit HCV in the blood from infecting organs capable of being infected such as liver again, and can lead the HCV patient to the recovery. However, as yet, infection-inhibiting substances for HCV-derived diseases have not been sufficiently studied.